Dejan Krajcar, Iztok Grabnar, Rebeka Jereb, Igor Legen, Jerneja Opara
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The objective of the present study was to evaluate predictive potential of various biopharmaceutical and pharmacokinetic parameters on the outcome of BE study.</p><p><strong>Methods: </strong>Retrospective analysis was performed on 198 Sandoz (Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526 Ljubljana, Slovenia) sponsored BE studies [52 active pharmaceutical ingredients (API)] where characteristics of BE study and APIs were collected for immediate-release products and their predictive potential on the study outcome was assessed using univariate statistical analysis.</p><p><strong>Results: </strong>Biopharmaceutics Classification System (BCS) was confirmed to be highly predictive of BE success. BE studies with poorly soluble APIs were riskier (23% non-BE) than with highly soluble APIs (0.1% non-BE). APIs with either lower bioavailability (BA), presence of first-pass metabolism, and/or being substrate for P-glycoprotein substrate (P-gP) were associated with higher non-BE occurrence. In silico permeability and time at peak plasma concentrations (T<sub>max</sub>) were shown as potentially relevant features for predicting BE outcome. In addition, our analysis showed significantly higher occurrence of non-BE results for poorly soluble APIs with disposition described by multicompartment model. 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引用次数: 2
摘要
背景和目的:了解进行早期生物等效性(BE)风险评估的参数的预测潜力对于产品开发期间的良好规划和风险缓解至关重要。本研究的目的是评估各种生物制药和药代动力学参数对BE研究结果的预测潜力。方法:回顾性分析198项山德士(Lek Pharmaceuticals d.d, A Sandoz Company, Verovskova 57, 1526 Ljubljana, Slovenia)赞助的BE研究[52种活性药物成分[API]，收集速释放产品的BE研究和API的特征，并使用单变量统计分析评估其对研究结果的预测潜力。结果:生物制药分类系统(BCS)被证实是be成功的高度预测。难溶性原料药的BE研究风险(23%非BE)高于高溶性原料药(0.1%非BE)。生物利用度(BA)较低、存在首过代谢和/或作为p -糖蛋白底物(P-gP)底物的原料药与较高的非be发生率相关。硅导率和峰值血浆浓度时间(Tmax)显示为预测BE预后的潜在相关特征。此外，我们的分析显示，对于多室模型描述的难溶性原料药，非be结果的发生率明显更高。在部分空腹BE研究中，关于难溶性原料药的结论是相同的;在饲料研究的一个子集中，BE组和非BE组的因素之间没有显著差异。结论:了解参数与BE结果的关联对于进一步开发早期BE风险评估工具非常重要，其中重点应首先寻找其他参数来区分一组难溶性api中的BE风险。
Predictive Potential of BCS and Pharmacokinetic Parameters on Study Outcome: Analysis of 198 In Vivo Bioequivalence Studies.
Background and objectives: Understanding predictive potential of parameters to perform early bioequivalence (BE) risk assessment is crucial for good planning and risk mitigation during product development. The objective of the present study was to evaluate predictive potential of various biopharmaceutical and pharmacokinetic parameters on the outcome of BE study.
Methods: Retrospective analysis was performed on 198 Sandoz (Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526 Ljubljana, Slovenia) sponsored BE studies [52 active pharmaceutical ingredients (API)] where characteristics of BE study and APIs were collected for immediate-release products and their predictive potential on the study outcome was assessed using univariate statistical analysis.
Results: Biopharmaceutics Classification System (BCS) was confirmed to be highly predictive of BE success. BE studies with poorly soluble APIs were riskier (23% non-BE) than with highly soluble APIs (0.1% non-BE). APIs with either lower bioavailability (BA), presence of first-pass metabolism, and/or being substrate for P-glycoprotein substrate (P-gP) were associated with higher non-BE occurrence. In silico permeability and time at peak plasma concentrations (Tmax) were shown as potentially relevant features for predicting BE outcome. In addition, our analysis showed significantly higher occurrence of non-BE results for poorly soluble APIs with disposition described by multicompartment model. The conclusions for poorly soluble APIs were the same on a subset of fasting BE studies; for a subset of fed studies there were no significant differences between factors in BE and non-BE groups.
Conclusion: Understanding the association of parameters and BE outcome is important for further development of early BE risk assessment tools where focus should be first in finding additional parameters to differentiate BE risk within a group of poorly soluble APIs.
期刊介绍：
Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences.
Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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